The present invention relates to a series of novel carbapenem derivatives, and provides methods and compositions using these for the treatment and prevention of bacterial infections; it also provides processes for their preparation.
The class of .beta.-lactam antibiotics includes the well known penicillins and cephalosporins, as well as the more recently introduced carbapenem compounds, of which the most successful member to date is imipenem (a derivative of the well known thienamycin), which is one of the isomers of 2-{2-[(iminomethyl)amino]ethylthio}-6-(1-hydroxyethyl)-1-carbapen-2-em-3-c arboxylic acid. In this specification, as is common in this field, the carbapenem derivatives, including those of the present invention, are named as derivatives of the notional 1-carbapen-2-em: ##STR4##
As can be seen from the above formula, the 1-carbapen-2-em system resembles the basic penicillin nucleus, except that there is a carbon atom (replacing a sulfur atom) at the 1-position. The carbapenem compounds also normally have substituents at the 2-, 3- and 6-positions. The substituent at the 6-position is most commonly, as in imipenem and thienamycin, a 1-hydroxyethyl group. These carbapenem compounds have a carbon-carbon double bond between the 2- and 3-positions.
In general, although thienamycin derivatives have been found to have excellent antibacterial activity, it has been reported that inactivation occurs in the human body as a result of decomposition of the compound due to the action of dehydropeptidase I; this is shown experimentally by a poor urinary recovery [H. Kropp et al: Antimicrob. Agents Chemother., 22, 62 (1982); S. R. Norrby et al.: ibid., 23, 300 (1983)]. As a consequence, the known thienamycin derivatives are of limited practical use. Although imipenem has been used clinically in combination with another compound, cilastatin, to protect it against this degradation, it is clearly undesirable to administer two or more drugs where one would suffice, and the restricted stability of the thienamycin derivatives has thus severely limited their use.
In recent years, many carbapenem derivatives have been disclosed for potential use as antibiotics, these generally differing in the nature of the substituent at the 2-position on the carbapenem nucleus. For example, European Patent Publications No. 126 587 and 333 175, which are believed to represent the closest prior art to the present invention of which we are presently aware, both disclose 1-carbapen-2-em-3-carboxylic acid derivatives having, like some of the compounds of the present invention, a substituted pyrrolidin-3-ylthio substituent at the 2-position. The compounds of the present invention differ from those of the prior art in possessing a quaternary nitrogen atom, and it appears that this results in a significant and unexpected increase in antimicrobial, especially antibacterial, activity as well as a much improved stability in the mammalian body, as demonstrated by improved urinary recovery. When comparing compounds of the type generally disclosed in the prior art with precisely equivalent compounds in which the nitrogen atom has been quaternised in accordance with the present invention, we have found a consistent improvement in urinary recovery in the compounds of the present invention as compared with the prior compounds. This activity is accompanied by a low toxicity, enabling the compounds to be used in therapy.
The compounds of the present invention are therefore expected to be of considerable value in the treatment and prophylaxis of microbial infections in mammals, especially humans.